Recent genetic evidence has shown that the age of onset of Alzheimer's disease (AD) correlates inversely with the concentration of the apolipoprotein E (apoE) variant 4. How the single amino acid change from variant 3 to variant 4 leads to neurodegeneration and tangles is not understood. There are two obvious routes of action of apoE that could lead to neurodegeneration; either, apoE4 could be entering the cell cytoplasm through a transmembrane flip process in the endocytic pathway or it could be inducing a signal that results in the degenerative process. We propose to follow the paths of uptake of apoE3 and E4 in dorsal root ganglion (DRG) neurons as well as the responses that they stimulate to differentiate between the possible mechanisms. Our long-term interest in neuronal transport and processing has stimulated us to address the question of the biological differences between apoE3 and E4 and how they might affect neuronal and biochemical differences between the two forms have been observed and we will determine if and how those differences can result in changes in cellular motility. Using specifically tagged apoEs and/or specific antibodies, we will follow the fate of the apoEs and the stimuli that they elicit. We will characterize the changes in axon extension and branching caused by apoE4 and will analyze its effect on microtubule- dependent motility. These studies will identify the cellular pathway of apoE processing and the bases of its effects on motility.